| 研究実績の概要 |
New strategies to produce covalent neuraminidase inhibitors were developed using two approaches: 1) synthetic biology, and 2) open-chain analogue synthesis.
In the first approach, synthetic biology approaches started with computational prediction of potential enzymes including sialic acid aldolase and sialic acid O-acetyltransferase, followed by the expression of their gene sequences in Escherichia coli, to produce necessary intermediates with C-2 fluorine. The selected O-acetyltransferase can also acetylate the sialic acid terminal oxygen, which is useful to produce potential coronavirus fusion inhibitors. Docking simulation indicates that our 8-O-acetylated sulfonamide has potential to bind coronavirus spike proteins. Machine learning prediction of keto acid decarboxylases identified additional enzymes to be tested for in vivo and in vitro decarboxylation of sialic acid.
In the second approach, open-chain analogues, especially those derived from sialic acid derived 4-(acetylamino)-2,4-dideoxy-D-glycero-D-galacto-octonic acid, were developed for C-1 and C-2 fluorine additions. Carboxy to thioester conversion was confirmed with isovaleric acid in a model reaction and sulfite addition to octanal results in the 8 carbon sulfonic acid as a bisulfite adduct with a C-1 hydroxy group. Also, addition of fluoromethyl phenyl sulfone to octanal results in a model sulfone with C-1 fluorine and C-2 hydroxy groups.
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